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Metabolism and Metabolomics

Metabolomic analysis of serum alpha-tocopherol among men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study

European Journal of Clinical Nutrition volume 76, pages 1254–1265 (2022)Cite this article

Subjects

Abstract

Background/Objectives

The role of vitamin E in chronic disease risk remains incompletely understood, particularly in an un-supplemented state, and evidence is sparse regarding the biological actions and pathways involved in its influence on health outcomes. Identifying vitamin-E-associated metabolites through agnostic metabolomics analyses can contribute to elucidating the specific associations and disease etiology. This study aims to investigate the association between circulating metabolites and serum α-tocopherol concentration in an un-supplemented state.

Subjects/Methods

Metabolomic analysis of 4,294 male participants was conducted based on pre-supplementation fasting serum in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The associations between 1,791 known metabolites measured by ultra-high-performance LC–MS/GC–MS and HPLC-determined α-tocopherol concentration were estimated using multivariable linear regression. Differences in metabolite levels per unit difference in α-tocopherol concentration were calculated as standardized β-coefficients and standard errors.

Results

A total of 252 metabolites were associated with serum α-tocopherol at the Bonferroni-corrected p value (p < 2.79 × 10−5). Most of these metabolites were of lipid and amino acid origin, with the respective subclasses of dicarboxylic fatty acids, and valine, leucine, and isoleucine metabolism, being highly represented. Among lipids, the strongest signals were observed for linoleoyl-arachidonoyl-glycerol (18:2/20:4)[2](β = 0.149; p = 8.65 × 10−146) and sphingomyelin (D18:2/18:1) (β = 0.035; p = 1.36 × 10−30). For amino acids, the strongest signals were aminoadipic acid (β = 0.021; p = 5.01 × 10−13) and l-leucine (β = 0.007; p = 1.05 × 10−12).

Conclusions

The large number of metabolites, particularly lipid and amino acid compounds associated with serum α-tocopherol provide leads regarding potential mechanisms through which vitamin E influences human health, including its role in cardiovascular disease and cancer.

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Fig. 1: Gaussian graphical models of metabolites among associated chemical super-pathways and sub-pathways most related to serum alpha-tocopherol concentration in the study.

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Code availability

The analytical methods for this study are available from the corresponding author upon appropriate request.

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Acknowledgements

We appreciate the participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study for their contributions to this research.

Funding

This research was supported by the Intramural Research Program of the US National Institutes of Health (NIH) National Cancer Institute.

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Authors and Affiliations

  1. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Wayne R. Lawrence, Jung-Eun Lim, Jiaqi Huang, Joshua N. Sampson, Stephanie J. Weinstein & Demetrius Albanes

  2. National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China

    Jiaqi Huang

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  1. Wayne R. Lawrence
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Contributions

Conception and design: WRL, JNS, DA. Development of methodology: WRL, JH, JNS, DA. Acquisition of data WRL, SJW, DA. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): WL, JL, JH, SJW, JNS, DA. Writing, review, and/or revision of the manuscript: WRL, JL, JH, JNS, SJW, DA.

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Correspondence to Wayne R. Lawrence or Demetrius Albanes.

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Lawrence, W.R., Lim, JE., Huang, J. et al. Metabolomic analysis of serum alpha-tocopherol among men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Eur J Clin Nutr 76, 1254–1265 (2022). https://doi.org/10.1038/s41430-022-01112-7

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